The invention relates to colloidal pharmaceutical carrier systems, comprising cyclosporin, for topical application on skin and mucous membrane, comprising a surfactant/co-surfactant mixture (polyoxyethylene glycerol monooleate/poloxamers), a hydrophilic phase, e.g. propylene glycol/water mixtures, a lipophilic phase (isopropyl palmitate or oleic acid) and penetration enhancers.
This invention relates in particular to pharmaceutical formulations comprising cyclosporin A (CsA) for topical application for the therapy of pathological changes of the skin, integumentary structures of the skin or the mucous membranes, in particular atopical dermatitis and psoriasis vulgaris, the use of these formulations and a method for production thereof.
It is known that CsA is a cyclic peptide comprising 11 amino acids, with a molar mass of 1202 g/mol, which is produced from the soil fungus tolypocladium inflatum. CsA is soluble in water only with great difficulty (<0.04 mg/ml at 25° C.), whereas it is readily soluble in oils and alcohols. Its immune-modulating effect is based on inhibiting the release of interleukin-1 from macrophages and of interleukin-2 from T-helper cells, which in turn activate cytotoxic T-precursor cells, from which the cytotoxic T-cells arise. The transcription of the genes which encode the mentioned cytokines is hereby inhibited. CsA only thereby affects the naturally occurring body defence to a small extent. From a galenic point of view, the pharmaceutical is a substance which is particularly unsuitable for topical therapy because the high lipophily makes penetration through the epidermal lipid barrier appear virtually impossible. There is indicated as a reason for the failure of previous attempts at production and application of different lipophilic, hydrophilic and liposomal preparations for topical application, generally inadequate penetration of the pharmaceutical.
In dermatology, CsA has proved to be particularly useful in systematic application for the treatment of severe psoriasis and atopical dermatitis. In addition, reports and studies exist with respect to the effectiveness after systemic application in the case of a multiplicity of further inflammatory dermatoses (e.g. dermatitis ulcerosa, lichen ruber, actinic reticuloid, disseminated granuloma annulare).
In WO 9302664, W/O microemulsions are described which contain a lipophilic phase (medium-chain triglycerides and a surfactant with a low HLB value in the ratio 5:1 to 1.5:1), an aqueous hydrophilic phase, a surfactant with a high HLB value and a water-soluble therapeutic agent.
GB 2222770 comprises microemulsion preconcentrates comprising CsA, a hydrophilic phase (propylene glycol or partial ether of low-molecular mono- or polyoxyalkane diols) (transcutol/glycofurol), a lipophilic phase (medium-chain triglycerides and a surfactant) (Cremophor RH 40). The systems are suitable for peroral application and improve the bioavailability compared with existing systems.
EP 760237 describes O/W microemulsions for water-insoluble pharmaceutically active substances such as CsA which are completely dissolved in the dispersed oil droplets. The systems comprise a C2-C20 substituted plant triglyceride, lecithin and another surfactant and a hydrophilic phase containing propylene glycol.
WO 97/22358 includes microemulsion preconcentrates with CsA, the pharmaceutical being dissolved in a system, comprising hydrophobic, (tocopherols or tocopherol derivatives) and hydrophilic components (propylene carbonate and polyethylene glycol with a molecular weight <1000) and also surfactant.
In WO 94/08603, WO 94/08605 and WO 99/39700, pharmaceutical formulations are described which cite cyclosporin and derivatives thereof as possible active ingredient in the colloidal system.
The previously described systems have however some substantial disadvantages. For solubilisation, partly organic solvents are used which must be removed subsequently again from the formulation without leaving any residue. Often, surfactant/co-surfactant combinations for improving the solubility of the pharmaceutical are used in too high concentrations (more than 20% m/m). Some publications mention systems which are not composed exclusively of skin-compatible ingredients. Some microemulsion preconcentrates are described, the actual structure of which is intended to be formed in situ only after application. Furthermore, the existing systems have much greater particle diameters.